An eminent jurist serving King St. Louis IX of France, Guido was ordained priest when his wife died c. 1256. He subsequently became bishop of Le Puy in 1257, archbishop of Narbonne in 1259, and cardinal in 1261. While on a diplomatic mission to England, he was elected pope in absentia on Feb. 5, 1265, and consecrated 10 days later. He centralized papal authority by decreeing that the jurisdiction over all appointments to western benefices belonged to Rome.

Clement executed the plan of Pope Urban IV, his predecessor, in a century-old battle between the papacy and the German Hohenstaufen (Hohenstaufen dynasty) family. For military and financial help against King Manfred of Sicily, a Hohenstaufen, Clement made Charles of Anjou king of Naples and Sicily in 1266. Having defeated and killed Manfred, Charles helped Clement eradicate Duke Conradin of Swabia, allied with the Italian Ghibellines (anti-papal political party) in 1268; thus, the Hohenstaufens were extinguished.

Clement's participation in the political affairs of Italy and Germany, however, brought peace neither to Rome nor to Italy. The Angevin dynasty founded by Charles was a new threat to the papacy's independence. Upon Clement's death, the papacy was vacant for nearly three years.